Heterocyclically substituted α-hydroxycarboxylic acid derivatives, method for producing the same and their use as endothelin receptor antagonists

ABSTRACT

The present invention relates to carboxylic acid derivatives of the formula I                    
     the substituents having the meanings explained in the description, preparation and use as endothelin receptor antagonists.

The present invention relates to novel carboxylic acid derivatives, their preparation and use.

Endothelin is a peptide constructed from 21 amino acids, which is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following text, “endothelin” or “ET” designates one or all isoforms of endothelin. Endothelin i s a potent vasoconstrictor and has a strong effect on the vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332 (1988), 411-415; FEBS Letters, 231 (1988), 440-444 and Biochem. Biophys. Res. Commun., 154 (1988), 868-875).

Increased or abnormal release of endothelin causes a lasting vascular contraction in peripheral, renal and cerebral blood vessels, which can lead to diseases. As reported in the literature, endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2 (1990), 207, J. Am. Med. Association 264 (1990), 2868, Nature 344 (1990), 114, N. Engl. J. Med. 322 (1989), 205, N. Engl. J. Med. 328 (1993), 1732, Nephron 66 (1994), 373, Stroke 25 (1994), 904, Nature 365 (1993), 759, J. Mol. Cell. Cardiol. 27 (1995), A234; Cancer Research 56 (1996), 663, Nature Medicine 1 (1995), 944).

At least two endothelin receptor subtypes, ETA and ETB receptors, have at present been described in the literature (Nature 348 (1990), 730, Nature 348 (1990), 732). Accordingly, substances which inhibit the binding of endothelin to one or both receptors should antagonize physiological effects of endothelin and therefore be useful pharmaceuticals.

It is an object of the present invention to provide endothelin receptor antagonists which bind to the ET_(A) and/or the ET_(B) receptor.

We have found that this object is achieved by heterocyclically substituted a-hydroxycarboxylic acid derivatives of the formula I

R₁ being tetrazole or a group

 where R has the following meanings:

a) a radical OR⁵, where R⁵ is:

hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerable organic ammonium ion such as tertiary C₁-C₄-alkylammonium or the ammonium ion;

C₃-C₈-cycloalkyl, C₁-C₈-alkyl, CH₂-phenyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, mercapto, C₁-C₄-alkylthio, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂;

a C₃-C₈-alkenyl or a C₃-C₈-alkynyl group, it being possible for these groups for their part to carry one to five halogen atoms;

R⁵ can furthermore be a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, mercapto, C₁-C₄-alkylthio, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂.

b) a 5-membered heteroaromatic linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl or triazolyl, which can carry one or two halogen atoms, or one or two C₁-C₄-alkyl or one or two C₁-C₄-alkoxy groups.

c) a group

 where k can assume the values 0, 1 or 2, p the values 1, 2, 3 or 4 and R⁶ is

C₁-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-alkenyl, C₃-C₈-alkynyl or phenyl, which can be mono- to trisubstituted by: halogen, nitro, cyano, C₁-C₄-alkyl, hydroxyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, mercapto.

d) a radical

 where R⁷ is:

C₁-C₄-alkyl, C₃-C₈-alkenyl, C₃-C₈-alkynyl, C₃-C₈-cycloalkyl, it being possible for these radicals to carry a C₁-C₄-alkoxy, C₁-C₄-alkylthio and/or a phenyl radical as mentioned under c);

C₁-C₄-haloalkyl or phenyl, which can be substituted as mentioned under c).

The other substituents have the following meanings:

A is NR⁸R⁹, azido, OR¹⁰, SR¹⁰ or C₁-C₄-alkyl.

X is oxygen, sulfur, CR¹¹ or NR¹²; with the proviso that if X=CR¹¹, then Y=oxygen or sulfur or NR¹⁴.

Y is oxygen, sulfur, CR¹³ or NR¹⁴; with the proviso that if Y=oxygen or sulfur or NR¹⁴, then X=CR¹¹.

R² and R³ (which can be identical or different):

are phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂ or phenyl, which can be mono- or polysubstituted, e.g. mono- to trisubstituted, by halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio; or

phenyl or naphthyl, which are connected to one another in the ortho-position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂, NH or N(C₁-C₄-alkyl) group;

C₅-C₆-cycloalkyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy.

and R¹¹ (which can be identical or different):

are hydrogen, halogen, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, hydroxyl, NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂; p2 C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, it being possible for these radicals to be substituted by halogen, hydroxyl, mercapto, carboxyl, cyano;

or CR⁴, together with CR¹¹, forms a 5- or 6-membered alkylene or alkenylene ring which can be unsubstituted or substituted, and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, —NH or —N(C₁-C₄-alkyl).

R⁸ is hydrogen, C₁-C₈-alkyl, C₃-C₈-alkenyl or C₃-C₈-alkynyl, C₁-C₅-alkylcarbonyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₁-C₄-alkoxycarbonyl, C₃-C₈-alkylcarbonylalkyl, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, C₃-C₈-cycloalkyl, phenoxy or phenyl, it being possible for the aryl radicals mentioned for their part to be mono- or polysubstituted, e.g. mono- to trisubstituted, by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, phenyl or C₁-C₄-alkylthio;

phenyl or naphthyl, which in each case can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, dioxomethylene or dioxoethylene;

C₃-C₈-cycloalkyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy;

or R⁸, together with R⁹, forms a C₃-C₇-alkylene chain closed to give a ring, which can be mono- or polysubstituted by C₁-C₄-alkyl, C₁-C₄-alkylthio, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, and in which an alkylene group can be replaced by oxygen or sulfur, such as —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₂—O—(CH₂)₂—, —(CH₂)₂—S—(CH₂)₂—.

R⁹ is hydrogen, C₁-C₄-alkyl;

or R⁹ is as indicated under R⁸ linked with R⁸ to give a ring.

R¹⁰ is hydrogen, C₁-C₈-alkyl, C₃-C₈-alkenyl or C₃-C₈-alkynyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₁-C₄-alkoxycarbonyl, C₃-C₈-alkylcarbonylalkyl, carboxamide, CONH(C₁-C₄-alkyl), CON(C₁-C₄-alkyl)₂, CONR¹⁵R¹⁶, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, C₃-C₈-cycloalkyl, heteroaryloxy or heteroaryl, which is five- or six-membered,

comprising one to three nitrogen atoms and/or a sulfur or oxygen atom, phenoxy or phenyl, it being possible for all aryl radicals mentioned, for their part, to be mono- or polysubstituted, e.g. mono- to trisubstituted, by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-alkylcarboxyl, R¹⁹, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, phenyl or C₁-C₄-alkylthio;

phenyl or naphthyl, which in each case can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, dioxomethylene or dioxoethylene;

C₃-C₈-cycloalkyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy.

R¹² is hydrogen, C₁-C₄-alkyl; or NR¹², together with CR⁴, forms a 5- or 6-membered alkylene or alkenylene ring which can be mono- to trisubstituted by C₁-C₄-alkyl, and in which in each case one or more methylene groups can be replaced by oxygen or sulfur.

R¹³ is hydrogen, halogen, C₁-C₄-alkyl, C₂-C₄-alkenyl, it being possible for these radicals to be substituted by halogen.

R¹⁴ is hydrogen, C₁-C₄-alkyl.

R¹⁵ and R¹⁶:

R¹⁵ and R¹⁶ together form a C₃-C₇-alkylene or C₄-C₇-alkenylene chain closed to give a ring, to which is fused a phenyl ring which can be mono- to trisubstituted by halogen, C₁-C₄-alkyl, C₁-C₄-alkylthio, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, hydroxyl, carboxyl, amino.

R¹⁹ is C₁-C₄-alkyl, C₁-C₄-alkylthio, C₁-C₄-alkoxy, which can carry one of the following radicals: hydroxyl, carboxyl, C₁-C₄-alkoxycarbonyl, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, carboxamide or CON(C₁-C₄-alkyl)₂.

The following definitions apply here and in the following text:

an alkali metal is, for example, lithium, sodium, potassium;

an alkaline earth metal is, for example, calcium, magnesium, barium;

C₃-C₈-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;

C₁-C₄-haloalkyl can be linear or branched, such as, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl;

C₁-C₄-haloalkoxy can be linear or branched, such as, for example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy;

C₁-C₄-alkyl can be linear or branched, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl;

C₂-C₄-alkenyl can be linear or branched, such as, for example, ethenyl, 1-propen-3-yl, 2-propen-3-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1-butenyl or 2-butenyl;

C₂-C₄-alkynyl can be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;

C₁-C₄-alkoxy can be linear or branched, such as, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy;

C₃-C₆-alkenyloxy can be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy;

C₃-C₆-alkynyloxy can be linear or branched, such as, for example, 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy;

C₁-C₄-alkylthio can be linear or branched, such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;

C₁-C₄-alkylcarbonyl can be linear or branched, such as, for example, acetyl, ethylcarbonyl or 2-propylcarbonyl;

C₁-C₄-alkoxycarbonyl can be linear or branched, such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl;

C₃-C₈-alkylcarbonylalkyl can be linear or branched, e.g. 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl;

C₁-C₈-alkyl can be linear or branched, such as, for example, C₁-C₄-alkyl, pentyl, hexyl, heptyl or octyl;

halogen is, for example, fluorine, chlorine, bromine, iodine.

The invention further relates to those compounds from which the compounds of the formula I can be released (prodrugs).

Preferred prodrugs are those in which the release proceeds under conditions such as prevail in certain body compartments, e.g. in the stomach, intestine, blood circulation, liver.

The invention further relates to the use of the abovementioned carboxylic acid derivatives for the production of drugs, in particular for the production of inhibitors for ET_(A) and ET_(B) receptors.

The compounds I and also the intermediates for their preparation, such as, for example, II, can have one or more asymmetrically substituted carbon atoms. Such compounds can be present as pure enantiomers or pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as the active compound is preferred.

The compounds having the formula IIa in which A is C₁-C₄-alkyl, azido, SR¹⁰ or OR¹⁰ can be prepared as described in WO 96/11914, DE 19614533.3 or DE 19726146.9.

Compounds of the formula IIb where A is SR¹⁰ or OR¹⁰ can be obtained in enantiomerically pure form via an acid-catalyzed transetherification, such as has been described in DE 19636046.3.

Enantiomerically pure compounds of the formula II can furthermore be obtained by carrying out a classical resolution with racemic or diastereomeric compounds of the formula II using suitable enantiomerically pure bases. Suitable bases of this kind are, for example, 4-chlorophenylethylamine and the bases which are mentioned in WO 96/11914.

The compounds Ia according to the invention, where A is C₁-C₄-alkyl, azido, SR¹⁰ or OR¹⁰ and the other substituents have the meaning given under the formula I, can be prepared, for example, by reacting the carboxylic acid derivatives of the formula IIa, where the substituents have the given meaning, with compounds of the formula III.

In formula III, R¹⁷ is halogen or R¹⁸—SO₂, it being possible for R¹⁸ to be C₁-C₄-alkyl, C₁-C₄-haloalkyl or phenyl. The reaction preferably takes place in an inert solvent or diluent with addition of a suitable base, i.e. of a base which brings about a deprotonation of the intermediate IIa, in a temperature range from room temperature up to the boiling point of the solvent.

Compounds of the type Ia where R¹=COOH can be obtained directly in this manner if the intermediate IIa, where R¹ is COOH, is deprotonated using two equivalents of a suitable base and reacted with compounds of the formula III. Here too, the reaction takes place in an inert solvent and in a temperature range from room temperature up to the boiling point of the solvent.

Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, which in each case may or may not be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers, such as, for example, diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitrites, such as, for example, acetonitrile and propionitrile, acid amides, such as, for example, dimethylformamide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane.

Compounds of the formula III are known or can be prepared in a generally known manner such as, for example:

H. Erlenmeyer, G. Bischoff, Helv. Chim. Acta, 29 (1946), 280-283, G. Kjellin, J. Sandstrom, Acta Chim. Scand., 23 (1969), 2879, E. R. Buchmann, A. O. Reims, H. Sargent, J. Org. Chem., 6 (1941), 764-766, F. C. James, H. D. Krebs, Aust. J. Chem., 35 (1982), 385-391, G. R. Humphrey, S. H. B. Wright, J. Heterocyclic Chem., 26 (1989), 23.

The base used can be an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, e.g. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.

Compounds of the formula IIb can be reacted similarly to the methods described in DE 19726146.9 to give the compounds Ib.

Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, i.e. compounds of the formula I where R¹ is COOH, and converting these first in a customary manner into an activated form such as an acid halide, an anhydride or imidazolide and then reacting this with an appropriate hydroxyl compound HOR⁵. This reaction can be carried out in the customary solvents and often necessitates the addition of a base, those mentioned above being suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide.

Additionally, compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, i.e. from compounds of the formula I where R¹ is a group COOM, it being possible for M to be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R—W, W being a customary nucleofugic leaving group, for example a halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl which is unsubstituted or substituted by halogen, alkyl or haloalkyl, such as, for example, toluenesulfonyl and methylsulfonyl or another equivalent leaving group. Compounds of the formula R—W having a reactive substituent W are known or easy to obtain using common expert knowledge. This reaction can be carried out in the customary solvents and is advantageously carried out with addition of a base, those mentioned above being suitable.

In some cases, the use of generally known protective group techniques is necessary for preparing the compounds I according to the invention. If, for example, R¹⁰=4-hydroxyphenyl, the hydroxyl group can first be protected as a benzyl ether, which is then cleaved at a suitable stage in the reaction sequence.

Compounds of the formula I where R¹ is tetrazole can be prepared as described in WO 96/11914.

With respect to the biological action, carboxylic acid derivatives of the formula I—both as pure enantiomers or pure diastereomers or as a mixture thereof—are preferred in which the substituents have the following meanings:

A is NR⁸R⁹, azido, OR¹⁰, SR¹⁰ or C₁-C₄-alkyl.

X is oxygen, sulfur, CR¹¹ or NR¹²; with the proviso that if X=CR¹¹, then Y=oxygen or sulfur or NR¹⁴.

Y is oxygen, sulfur, CR¹³ or NR¹⁴; with the proviso that if Y=oxygen or sulfur or NR¹⁴, then X=CR¹¹.

R² and R³ (which can be identical or different):

are phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, cyano, hydroxyl, mercapto, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, NH(C₁-C₄-alkyl) or N(C₁-C₄-alkyl)₂ or phenyl, which can be mono- to trisubstituted by halogen, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio; or

phenyl or naphthyl, which are connected to one another in the ortho-position by a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂, NH or N(C₁-C₄-alkyl) group;

C₅-C₆-cycloalkyl, it being possible for these radicals in each case to be mono- to tri-substituted by: halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy.

R⁴ and R¹¹ (which can be identical or different):

are C₁-C₄-alkyl, it being possible for these radicals to be substituted by halogen, hydroxyl;

hydrogen, halogen, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, hydroxyl, NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂;

or CR⁴, together with CR¹¹, forms a 5- or 6-membered alkylene or alkenylene ring which can be mono- to trisubstituted by C₁-C₄-alkyl and in which in each case one to three methylene groups can be replaced by oxygen or sulfur.

R⁸ is hydrogen, C₁-C₈-alkyl, C₁-C₅-alkylcarbonyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, hydroxyl, carboxyl, amino, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₁-C₄-alkoxycarbonyl, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, C₅-C₆-cycloalkyl, phenoxy or phenyl, it being possible for the aryl radicals mentioned, for their part, to be mono- to trisubstituted by halogen, hydroxyl, C₁-C₄-alkyl,

C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, phenyl or C₁-C₄-alkylthio;

phenyl or naphthyl, which in each case can be mono- to trisubstituted by halogen, hydroxyl, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, dioxomethylene or dioxoethylene;

C₃-C₈-cycloalkyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy;

or R₈, together with R⁹, forms a C₄-C₆-alkylene chain closed to give a ring, which can be mono- to trisubstituted by C₁-C₄-alkyl, C₁-C₄-haloalkyl, and in which an alkylene group can be replaced by oxygen or sulfur, such as —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₂—O—(CH₂)₂—, —(CH₂)₂—S—(CH₂)₂—.

R⁹ is hydrogen, C₁-C₄-alkyl;

or R⁹ is as given under R⁸ linked with R⁸ to give a ring.

R¹⁰ is hydrogen, C₁-C₈-alkyl, C₃-C₈-alkenyl or C₃-C₈-alkynyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, hydroxyl, mercapto, carboxyl, amino, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₁-C₄-alkoxycarbonyl, carboxamide, CONH(C₁-C₄-alkyl), CON(C₁-C₄-alkyl)₂, CONR¹⁵R¹⁶, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, C₅-C₆-cycloalkyl, phenoxy or phenyl, it being possible for the aryl radicals mentioned for their part to be mono- to trisubstituted by halogen, hydroxyl, C₁-C₄-alkyl, C₁-C₄-alkylcarboxyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, phenyl, C₁-C₄-alkylthio or R¹⁹;

phenyl or naphthyl, which in each case can be mono- to trisubstituted by: halogen, hydroxyl, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, dioxomethylene or dioxoethylene;

C₃-C₈-cycloalkyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl.

R¹² is hydrogen, methyl; or

NR¹², together with CR⁴, forms a 5- or 6-membered alkylene ring which can be mono- to trisubstituted by methyl.

R¹³ is hydrogen, halogen, C₁-C₄-alkyl, it being possible for these radicals to be mono- to trisubstituted by halogen.

R¹⁴ is hydrogen, methyl.

R¹⁵ and R¹⁶:

R¹⁵ and R¹⁶ together form a C₃-C₇-alkylene chain or C₄-C₇-alkenylene chain closed to give a ring, to which a phenyl ring is fused, such as 7-aza-bicyclo [4.2.0]-octa-1,3,5-triene, 2,3-dihydroindole, indole, 1,3-dihydroisoindole, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, it being possible in each case for the phenyl ring to be mono- to trisubstituted by halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy.

R¹⁹ is methyl, ethyl, methoxy or ethoxy, which carry one of the following radicals: hydroxyl, carboxyl, C₁-C₄-alkoxycarbonyl, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, carboxamide or CON(C₁-C₄-alkyl)₂.

Particularly preferred compounds of the formula I (both as pure enantiomers or pure diastereomers or as a mixture thereof—are those in which the substituents have the following meanings:

A is NR⁸R⁹, azido, OR¹⁰, SR¹⁰ or C₁-C₄-alkyl

X is oxygen, sulfur or CR¹¹; with the proviso that if X=CR¹¹, then Y=oxygen or sulfur.

Y is oxygen, sulfur or CR¹³; with the proviso that if Y=oxygen or sulfur, then X=CR¹¹.

R² and R³ (which can be identical or different):

are phenyl or naphthyl, which in each case can be mono- to trisubstituted by: halogen, hydroxyl, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, phenoxy or phenyl, which can be mono- to trisubstituted by halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy or C₁-C₄-haloalkoxy; or

phenyl or naphthyl, which are connected to one another in the ortho-position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂, NH or N(C₁-C₄-alkyl) group;

cyclohexyl.

R⁴ and R¹¹ (which can be identical or different):

are hydrogen, halogen, C₁-C₄-alkyl, trifluoromethyl, hydroxymethylene, C₁-C₄-alkoxy, C₁-C₄-alkylthio, N(C₁-C₄-alkyl)₂;

or CR⁴, together with CR¹¹, forms a 5- or 6-membered alkylene or alkenylene ring which can be mono- or disubstituted by methyl, and in which in each case a methylene group can be replaced by oxygen;

R⁸ is hydrogen, C₁-C₄-alkyl, C₁-C₄-alkylcarbonyl, it being possible for these radicals to mono- to trisubstituted by: halogen, hydroxyl, carboxyl, amino, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₁-C₄-alkoxycarbonyl, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, C₅-C₆-cycloalkyl, phenyl, which for its part can be mono- to trisubstituted by halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio;

phenyl which can be mono- to trisubstituted by halogen, hydroxyl, C₁-C₄-alkyl, trifluoromethyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, dioxomethylene or dioxoethylene; C₅-C₆-cycloalkyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy;

or R⁸, together with R⁹, forms a C₄-C₆-alkylene chain closed to give a ring, which can be mono- to trisubstituted by C₁-C₄-alkyl, C₁-C₄-haloalkyl, and in which an alkylene group can be replaced by oxygen, such as —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₂—O—(CH₂)₂—.

R⁹ is hydrogen, C₁-C₄-alkyl;

or R⁹ is as indicated under R⁸ linked with R⁸ to give a ring.

R¹⁰ is hydrogen, C₁-C₄-alkyl, it being possible for these radicals in each case to be mono- to trisubstituted by: halogen, hydroxyl, carboxyl, C₁-C₄-alkoxy, C₁-C₄-alkoxycarbonyl, carboxamide, CONH(C₁-C₄-alkyl), CON(C₁-C₄-alkyl)₂, CONR¹⁵R¹⁶, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, C₅-C₆-cycloalkyl, phenyl, which for its part can be mono- to trisubstituted by halogen, hydroxyl, C₁-C₄-alkyl, C₁-C₄-alkylcarboxyl, trifluoromethyl, C₁-C₄-alkoxy, NH(C₁-C₄-alkyl), R¹⁹, N(C₁-C₄-alkyl)₂, phenyl or C₁-C₄-alkylthio;

phenyl which can be mono- to trisubstituted by halogen, hydroxyl, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, dioxomethylene or dioxoethylene;

C₃-C₈-cycloalkyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy.

R¹³ is hydrogen, halogen, C₁-C₄-alkyl, trifluoromethyl.

R¹⁵ and R¹⁶:

R¹⁵ and R¹⁶ together form a C₃-C₇-alkylene chain closed to give a ring, to which a phenyl ring is fused, such as 2,3-dihydroindole, indole, 1,3-dihydroisoindole, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, it being possible for the phenyl ring in each case to be mono- to trisubstituted by halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, hydroxyl;

R¹⁹ is methoxy or ethoxy, which carry one of the following radicals: hydroxyl, carboxyl, C₁-C₄-alkoxycarbonyl, amino, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, carboxamide or CON(C₁-C₄-alkyl)₂.

The compounds of the present invention offer a novel therapeutic potential for the treatment of hypertension, high pulmonary pressure, myocardial infarct, angina pectoris, arrhythmia, acute/chronic kidney failure, chronic cardiac insufficiency, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and bypass operations, benign prostate hyperplasia, kidney failure or hypertension caused by ischemia and by intoxication, metastasis and growth of mesenchymal tumors such as prostate carcinoma, contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcers.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and inhibitors of the renin-angiotension system. Inhibitors of the renin-angiotension system are renin inhibitors, angiotension II antagonists and angiotension-converting enzyme (ACE) inhibitors. Combinations of endothelin receptor antagonists of the formula I and ACE inhibitors are preferred.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and calcium antagonists such as verapamil.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and beta-blockers.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and diuretics.

The invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor). Such substances are, for example, antibodies directed against VEGF or specific binding proteins or alternatively low molecular weight substances which can specifically inhibit VEGF release or receptor binding.

The abovementioned combinations can be administered simultaneously or sequentially. They can be employed both in a single pharmaceutical formulation or alternatively in separate formulations. The administration form can also be different, for example the endothelin receptor antagonists can be administered orally and VEGF inhibitors parenterally.

These combination preparations are especially suitable for the treatment and prevention of hypertension and its sequelae and also for the treatment of cardiac insufficiency.

The good action of the compounds can be seen in the following experiments:

Receptor Binding Studies

For binding studies, cloned human ET_(A) or ET_(B) receptor-expressing CHO cells were employed.

Membrane Preparation

The ET_(A) or ET_(B) receptor-expressing CHO cells were proliferated in DMEM NUT MIX F₁₂ medium (Gibco, No. 21331-020) using 10% fetal calf serum (PAA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U/ml of penicillin and 100 μg/ml of streptomycin (Gibco, Sigma No P-0781). After 48 hours, the cells were washed with PBS and incubated at 37° C. for 5 minutes with 0.05% trypsin-containing PBS. Neutralization with medium was then carried out and the cells were collected by centrifugation at 300×g.

For the membrane preparation, the cells were adjusted to a concentration of 10⁸ cells/ml of buffer (50 mM tris·HCL buffer, pH 7.4) and then disintegrated by means of ultrasound Branson Sonifier 250, 40-70 seconds/constant/output [sic] 20).

Binding Tests

For the ET_(A) and ET_(B) receptor binding test, the membranes were suspended in incubation buffer (50 mM tris HCl, pH 7.4 with 5 mM MnCl₂, 40 mg/ml of bacitracin and 0.2% BSA) in a concentration of 50 μg of protein per test batch and incubated at 25° C. with 25 pM [125I]-ET₁ (ET_(A) receptor test) or 25 pM [125I]-ET₃ (ET_(B) receptor test) in the presence or absence of test substance. The nonspecific binding was determined with 10⁻⁷ M ET₁. After 30 min, the free and the bound -radioligand were separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters were washed with ice-cold tris HCl buffer, pH 7.4 with 0.2% BSA.

The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Testing of the ET Antagonists in Vivo:

Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were catheterized.

In control animals, the intravenous administration of 1 mg/kg of ET1 leads to a clear blood pressure rise, which lasts for a relatively long period.

The test animals were injected i.v. (1 ml/kg) with the test compounds 30 min before ET1 administration. To determine the ET-antagonistic properties, the blood pressure changes in the test animals were compared with the those in the control animals.

p.o. Testing of the Mixed ET_(A) and ET_(B) antagonists:

Male normotonic rats (Sprague Dawley, Janvier) weighing 250-350 g are orally pretreated with the test substances. 80 minutes later, the animals are anesthetized with urethane and the carotid artery is catheterized (for blood pressure measurement) and also the jugular vein (administration of big endothelin/endothelin 1).

After a stabilization phase, big endothelin (20 μg/kg, admr. vol. 0.5 ml/kg) or ET1 (0.3 μg/kg, admr. vol. 0.5 ml/kg) is given intravenously. Blood pressure and heart rate are recorded continuously for 30 minutes. The clear and long-lasting blood pressure changes are calculated as the area under the curve (AUC). To determine the antagonistic action of the test substances, the AUC of the substance-treated animals is compared with the AUC of the control animals.

The compounds according to the invention can be administered orally or parentally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a customary manner. Administration can also be carried out through the nasopharynx using vapors or sprays.

The dose depends on the age, condition and weight of the patient and also on the manner of administration. As a rule, the daily active compound dose is from approximately 0.5 to 100 mg/kg of body weight in the case of oral administration and from approximately 0.1 to 10 mg/kg of body weight in the case of parenteral administration.

The novel compounds can be administered in solid or liquid form in the conventional pharmaceutical administration forms, e.g. as tablets, film-coated tablets, capsules, powders, granules, coated tablets, suppositories, solutions, ointments, creams or sprays. These are prepared in a customary manner. The active compounds can in this case be processed with the customary pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow-regulating agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-delaying agents, antioxidants and/or propellants (cf. H. Sucker et al.: Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1991). The application forms thus obtained normally contain the active compound in an amount from 0.1 to 90% by weight.

SYNTHESIS EXAMPLES Example 1 2-Methylsulfonyl-4,5-dimethylthiazole

2.7 g of 2-methylmercapto-4,5-dimethylthiazole were initially introduced into methylene chloride at ice temperature and 5.9 g of mCPBA were added. The batch was stirred at room temperature for 16 hours and then extracted once with sodium hydrogen-carbonate solution and with sodium thiosulfate solution. The organic phase was dried over magnesium sulfate, the solvent was distilled off and 2.88 g of oil were isolated, which were directly employed further.

¹H-NMR (200 MHz): 3.25 ppm (3 H, s), 2.50(3 H, s), 2.40 (3 H, s). ESI-MS: M⁺=191.

Example 2 2-Methylmercapto-4,5-cyclopentenothiazole

10.4 g of ammonium dithiocarbamate were initially introduced into ethanol and 7.5 g of 2-chlorocyclopentanone were added. After 30 minutes, the reaction was complete and the reaction mixture was added to water. The aqueous phase was rendered strongly alkaline using sodium hydroxide solution, extracted with methylene chloride and then adjusted to pH 2 using concentrated hydrochloric acid. The aqueous phase was extracted with ethyl acetate, the organic phase was dried with magnesium sulfate and the solvent was distilled off. The residue was taken up in toluene, a spatula tipful of p-toluenesulfonic acid was added and the solvent was distilled off at 60° C. 7.9 g of oil were dissolved in 75 ml of water and 2.4 g of NaOH and 5.7 ml of dimethyl sulfate were rapidly added dropwise. After one hour, the reaction was complete and the mixture was added to water. The aqueous phase was extracted with ether, the organic phase was dried with magnesium sulfate and the solvent was distilled off. The residue was employed in the following reaction without further purification.

Example 3 2-Methylsulfonyl-4,5-cyclopentenothiazole

1.9 g of 2-methylmercapto-4,5-cyclopentenothiazole were initially introduced at ice temperature into methylene chloride and 7.3 g of mCPBA were added. The batch was stirred at room temperature for 16 hours and then extracted once with 1 N sodium hydroxide solution and with sodium thiosulfate solution. The organic phase was dried over magnesium sulfate, the solvent was distilled off and 2.25 g of oil were isolated, which were directly employed further.

¹H-NMR (200 MHz): 3.26 ppm (3 H, s), 3.05 (2 H, dd), 2.95(2 H, dd), 2.55 (2 H, dddd). ESI-MS: M⁺=203.

Example 4 2-Methylsulfonyl-4,5-dimethyloxazole

3 g of 2-methylthio-4,5-dimethyloxazole were dissolved in 100 ml of methylene chloride and 13 g of mCPBA were added at ice temperature. The batch was stirred for three hours and then added to sodium thiosulfate solution. It was neutralized with sodium hydrogencarbonate and the product was extracted with methylene chloride. After drying over magnesium sulfate, the solvent was distilled off and 2 g of crude product were isolated, which it was directly possible to employ further.

¹H-NMR (200 MHz): 3.30 ppm (3 H, s), 2.35(3 H, s), 2.15 (3 H, s). ESI-MS: M⁺=175.

Example 5 (S)-2-(4,5-Dimethylthiazol-2-yloxy)-3-methoxy-3,3-diphenyl-propionic Acid (I-1)

320 mg of 55% NaH were added to an initial mixture of 1 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in 20 ml of THF/20 ml of DMF and the mixture was stirred for 15 minutes. 700 mg of 2-methylsulfonyl-4,5-dimethylthiazole were added to this mixture and it was stirred at room temperature for 16 hours. The batch was then treated with water, the mixture was acidified with citric acid and the product was extracted with ether. After drying over magnesium sulfate and distilling off the solvent, it was purified chromatographically and the product was crystallized from ether/n-hexane. 522 mg of crystals were isolated.

¹H-NMR (200 MHz): 7.35-7.20 ppm (10 H, m), 6.25 (1 H, s), 3.30 (3 H, s), 2.25(3 H, s), 2.20 (3 H, s). ESI-MS: M⁺=383.

Example 6 2-(4,5-Cyclopentenothiazol-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)-ethoxy)-3,3-diphenylpropionic Acid (I-17)

¹H-NMR (200 MHz): 7.30-7.20 ppm (10 H, m), 6.80-6.60 (3 H, m), 6.25 (1 H, s), 3.85 (3 H, s), 3.80 (3 H, s), 3.70-3.40 (2 H, m), 2.9-2.6 (4 H, m), 2.30-2.25 (2 H, m). ESI-MS: M⁺=545.

2-(4,5-Dimethyloxazol-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)-ethoxy)-3,3-diphenylpropionic Acid (I-15)

¹H-NMR (200 MHz): 7.30-7.20 ppm (10 H, m), 6.80-6.60 (3 H, m), 6.00 (1 H, s), 3.85 (3 H, s), 3.80 (3 H, s), 3.70-3.40 (2 H, m), 2.80 (2 H, tr), 2.10 (3 H, s), 1.90 (3 H, s). ESI-MS: M⁺=517.

(S)-2-(Benzothiazol-2-yloxy)-3-methoxy-3,3-diphenylpropionic Acid (I-6)

¹H-NMR (200 MHZ): 7.70-7.50 (2 H, m), 7.35-7.20 (12 H, m), 6.50 (1 H, s), 3.30 (3 H, s). ESI-MS: M⁺=405.

(S)-2-(4,5-Cyclopentenothiazol-2-yloxy)-3-methoxy-3,3-diphenyl-propionic Acid (I-5)

¹H-NMR (200 MHz): 7.50-7.20 ppm (10 H, m), 6.40 (1 H, s), 3.30 (3 H, s), 2.80-2.60 (4 H, m), 2.30 (2 H, m). ESI-MS: M⁺=395.

(S)-2-(4,5-Dimethyloxazol-2-yloxy)-3-methoxy-3,3-diphenyl-propionic Acid (I-4)

¹H-NMR (200 MHz): 7.50-7.20 ppm (10 H, m), 6.10 (1 H, s), 3.25 (3 H, s), 2.1 (3H, s), 1.90 (3 H, S). ESI-MS: M⁺=367.

2-(4,5-Dimethylthiazol-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)-ethoxy)-3,3-diphenylpropionic Acid (I-13)

¹H-NMR (200 MHz): 7.30-7.20 ppm (10 H, m), 6.70-6.50 (3 H, m), 6.20 (1 H, s), 3.90 (3 H, s), 3.85 (3 H, s), 3.70-3.40 (2 H, m), 2.80 (2 H, tr), 2.20 (3 H, s), 1.15 (3 H, s). ESI-MS: M⁺=533.

The compounds in Table I can be prepared similarly or as described in the general section.

TABLE I

No. R¹ R², R³ A X R⁴ Y I-1 COOH phenyl MeO CMe Me S I-2 COOH 4-Cl-phenyl MeO CMe Me S I-3 COOH 4-F-phenyl MeO CMe Me S I-4 COOH phenyl MeO CMe Me O I-5 COOH phenyl MeO C—CH₂—CH₂—CH₂ S I-6 COOH phenyl MeO C—CH═CH—CH═CH S I-7 COOH phenyl (4-MeO-phenyl)CH₂CH₂O CMe Me S I-8 COOH phenyl (4-MeO-phenyl)CH₂CH₂O CMe Me O I-9 COOH 4-F-phenyl (4-MeO-phenyl)CH₂CH₂O CMe Me S I-10 COOH 4-Cl-phenyl (4-MeO-phenyl)CH₂CH₂O CMe Me O I-11 COOH phenyl (4-MeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-12 COOH phenyl (4-MeO-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-13 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me S I-14 COOH 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me S I-15 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me O I-16 COOH 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-17 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-18 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-19 COOH phenyl (4-MeO-phenyl)CH₂O CMe Me S I-20 COOH 4-F-phenyl (4-MeO-phenyl)CH₂O CMe Me S I-21 COOH 4-Cl-phenyl (4-MeO-phenyl)CH₂O CMe Me S I-22 COOH phenyl (4-MeO-phenyl)CH₂O CMe Me O I-23 COOH phenyl (4-MeO-phenyl)CH₂O C—CH₂—CH₂—CH₂ S I-24 COOH phenyl (4-MeO-phenyl)CH₂O C—CH═CH—CH═CH S I-25 COOH phenyl (4-MeO-phenyl) O CMe Me S I-26 COOH phenyl (4-MeO-phenyl) O CMe Me O I-27 COOH phenyl (4-MeO-phenyl) O C—CH₂—CH₂—CH₂ S I-28 COOH phenyl (4-MeO-phenyl) O C—CH═CH—CH═CH S I-29 COOH phenyl (3-MeO-4-HO₂CCH₂O-phenyl)CH₂CH₂O CMe Me S I-30 COOH 4-Cl-phenyl (3-MeO-4-HO₂CCH₂O-phenyl)CH₂CH₂O CMe Me S I-31 COOH phenyl (3-MeO-4-HO₂CCH₂O-phenyl)CH₂CH₂O CMe Me O I-32 COOH 4-F-phenyl (3-MeO-4-HO₂CCH₂O-phenyI)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-33 COOH phenyl (3-MeO-4-HO₂CCH₂O-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-34 COOH phenyl (3-MeO-4-HO₂CCH₂O-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-35 COOH 4-F-phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O CMe Me S I-36 COOH phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O CMe Me S I-37 COOH phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O CMe Me O I-38 COOH 4-Cl-phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-39 COOH phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-40 COOH phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-41 COOH phenyl (3-MeO-4-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O CMe Me S I-42 COOH 4-F-phenyl (3-MeO-4-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O CMe Me S I-43 COOH 4-Cl-phenyl (3-MeO-4-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O CMe Me S I-44 COOH phenyl (3-MeO-4-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O CMe Me O I-45 COOH phenyl (3-MeO-4-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-46 COOH phenyl (3-MeO-4-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-47 COOH phenyl (4-HO₂C-phenyl)CH₂CH₂O CMe Me S I-48 COOH phenyl (4-HO₂C-phenyl)CH₂CH₂O CMe Me O I-49 COOH phenyl (4-HO₂C-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-50 COOH phenyl (4-HO₂C-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-51 COOH phenyl (4-HO₂C-phenyl)CH₂O CMe Me S I-52 COOH phenyl (4-HO₂C-phenyl)CH₂O CMe Me O I-53 COOH 4-F-phenyl (4-HO₂C-phenyl)CH₂O C—CH₂—CH₂—CH₂ S I-54 COOH phenyl (4-HO₂C-phenyl)CH₂O C—CH₂—CH₂—CH₂ S I-55 COOH phenyl (4-HO₂C-phenyl)CH₂O C—CH═CH—CH═CH S I-56 COOH phenyl (4-Me-phenyl)O CMe Me S I-57 COOH 4-F-phenyl (4-Me-phenyl)O CMe Me S I-58 COOH 4-Cl-phenyl (4-Me-phenyl)O CMe Me S I-59 COOH phenyl (4-Me-phenyl)O CMe Me O I-60 COOH phenyl (4-Me-phenyl)O C—CH₂—CH₂—CH₂ S I-61 COOH phenyl (4-Me-phenyl)O C—CH═CH—CH═CH S I-62 COOH phenyl (4-Me-phenyl)CH₂O CMe Me S I-63 COOH phenyl (4-Me-phenyl)CH₂O CMe Me O I-64 COOH phenyl (4-Me-phenyl)CH₂O C—CH₂—CH₂—CH₂ S I-65 COOH 4-F-phenyl (4-Me-phenyl)CH₂O C—CH₂—CH₂—CH₂ S I-66 COOH phenyl (4-Me-phenyl)CH₂O C—CH═CH—CH═CH S I-67 COOH phenyl (4-Cl-phenyl)CH₂CH₂O CMe Me S I-68 COOH phenyl (4-Cl-phenyl)CH₂CH₂O CMe Me O I-69 COOH phenyl (4-Cl-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-70 COOH phenyl (4-Cl-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-71 COOH phenyl (4-Me-phenyl)CH₂CH₂O CMe Me S I-72 COOH phenyl (4-Me-phenyl)CH₂CH₂O CMe Me O I-73 COOH phenyl (4-Me-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-74 COOH phenyl (4-Me-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-75 COOH phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O CMe Me S I-76 COOH 4-Cl-phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O CMe Me S I-77 COOH 4-F-phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O CMe Me S I-78 COOH phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O CMe Me O I-79 COOH phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-80 COOH phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-81 COOH phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O CMe Me S I-82 COOH 4-F-phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O CMe Me S I-83 COOH 4-Cl-phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O CMe Me S I-84 COOH phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O CMe Me O I-85 COOH phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-86 COOH phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-87 COOH phenyl (3-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O CMe Me S I-88 COOH phenyl (3-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O CMe Me O I-89 COOH phenyl (3-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-90 COOH phenyl (3-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-91 COOH phenyl N-Me-N-phenyl-NOCCH₂O CMe Me S I-92 COOH 4-F-phenyl N-Me-N-phenyl-NOCCH₂O CMe Me S I-93 COOH 4-Cl-phenyl N-Me-N-phenyl-NOCCH₂O CMe Me S I-94 COOH phenyl N-Me-N-phenyl-NOCCH₂O CMe Me O I-95 COOH phenyl N-Me-N-phenyl-NOCCH₂O C—CH₂—CH₂—CH₂ S I-96 COOH phenyl N-Me-N-phenyl-NOCCH₂O C—CH═CH—CH═CH S I-97 COOH phenyl N-Bu-N-phenyl-NOCCH₂O CMe Me S I-98 COOH 4-F-phenyl N-Bu-N-phenyl-NOCCH₂O CMe Me S I-99 COOH 4-Cl-phenyl N-Bu-N-phenyl-NOCCH₂O CMe Me S I-100 COOH phenyl N-Bu-N-phenyl-NOCCH₂O CMe Me O I-101 COOH phenyl N-Bu-N-phenyl-NOCCH₂O C—CH₂—CH₂—CH₂ S I-102 COOH phenyl N-Bu-N-phenyl-NOCCH₂O C—CH═CH—CH═CH S I-103 COOH phenyl Bu₂NOCCH₂O CMe Me S I-104 COOH phenyl Bu₂NOCCH₂O CMe Me S I-105 COOH 4-F-phenyl Bu₂NOCCH₂O CMe Me S I-106 COOH 4-Cl-phenyl Bu₂NOCCH₂O CMe Me O I-107 COOH phenyl Bu₂NOCCH₂O C—CH₂—CH₂—CH₂ S I-108 COOH phenyl Bu₂NOCCH₂O C—CH═CH—CH═CH S I-109 COOH phenyl phenyl-HNOCCH₂O CMe Me S I-110 COOH 4-Cl-phenyl phenyl-HNOCCH₂O CMe Me S I-111 COOH 4-F-phenyl phenyl-HNOCCH₂O CMe Me S I-112 COOH phenyl phenyl-HNOCCH₂O CMe Me O I-113 COOH phenyl phenyl-HNOCCH₂O C—CH₂—CH₂—CH₂ S I-114 COOH phenyl phenyl-HNOCCH₂O C—CH═CH—CH═CH S I-115 COOH phenyl (2,6-diethyl-phenyl)-HNOCCH₂O CMe Me S I-116 COOH 4-Cl-phenyl (2,6-diethyl-phenyl)-HNOCCH₂O CMe Me S I-117 COOH 4-F-phenyl (2,6-diethyl-phenyl)-HNOCCH₂O CMe Me S I-118 COOH phenyl (2,6-diethyl-phenyl)-HNOCCH₂O CMe Me O I-119 COOH phenyl (2,6-diethyl-phenyl)-HNOCCH₂O C—CH₂—CH₂—CH₂ S I-120 COOH phenyl (2,6-diethyl-phenyl)-HNOCCH₂O C—CH═CH—CH═CH S I-121 COOH phenyl (—CH₂CH₂CH₂CH₂CH₂CH₂—)NOCCH₂O CMe Me S I-122 COOH phenyl (—CH₂CH₂CH₂CH₂CH₂CH₂—)NOCCH₂O CMe Me O I-123 COOH phenyl (—CH₂CH₂CH₂CH₂CH₂CH₂—)NOCCH₂O C—CH₂—CH₂—CH₂ S I-124 COOH phenyl (—CH₂CH₂CH₂CH₂CH₂CH₂—)NOCCH₂O C—CH═CH—CH═CH S I-125 COOH phenyl (—CH₂CH₂CH₂CH₂—)NOCCH₂O CMe Me S I-126 COOH phenyl (—CH₂CH₂CH₂CH₂—)NOCCH₂O CMe Me O I-127 COOH phenyl (—CH₂CH₂CH₂CH₂—)NOCCH₂O C—CH₂—CH₂—CH₂ S I-128 COOH phenyl (—CH₂CH₂CH₂CH₂—)NOCCH₂O C—CH═CH—CH═CH S I-129 COOH phenyl Me CMe Me S I-130 COOH 4-F-phenyl Me CMe Me S I-131 COOH 4-Cl-phenyl Me CMe Me S I-132 COOH phenyl Me CMe Me O I-133 COOH phenyl Me C—CH₂—CH₂—CH₂ S I-134 COOH phenyl Me C—CH═CH—CH═CH S I-135 COOH phenyl MeS CMe Me S I-136 COOH 4-F-phenyl MeS CMe Me S I-137 COOH 4-Cl-phenyl MeS CMe Me S I-138 COOH phenyl MeS CMe Me O I-139 COOH 4-F-phenyl MeS C—CH₂—CH₂—CH₂ S I-140 COOH phenyl MeS C—CH₂—CH₂—CH₂ S I-141 COOH phenyl MeS C—CH═CH—CH═CH S I-142 COOH phenyl CH₃CONH CMe Me S I-143 COOH 4-F-phenyl CH₃CONH CMe Me S I-144 COOH 4-Cl-phenyl CH₃CONH CMe Me S I-145 COOH phenyl CH₃CONH CMe Me O I-146 COOH phenyl CH₃CONH C—CH₂—CH₂—CH₂ S I-147 COOH phenyl CH₃CONH C—CH═CH—CH═CH S I-148 COOH phenyl (CH₃)₃CCONH CMe Me S I-149 COOH 4-F-phenyl (CH₃)₃CCONH CMe Me S I-150 COOH 4-Cl-phenyl (CH₃)₃CCONH CMe Me S I-151 COOH phenyl (CH₃)₃CCONH CMe Me O I-152 COOH phenyl (CH₃)₃CCONH C—CH₂—CH₂—CH₂ S I-153 COOH phenyl (CH₃)₃CCONH C—CH═CH—CH═CH S I-154 COOH phenyl (—CH₂CH₂—)CHCONH CMe Me S I-155 COOH phenyl (—CH₂CH₂—)CHCONH CMe Me O I-156 COOH phenyl (—CH₂CH₂—)CHCONH C—CH₂—CH₂—CH₂ S I-157 COOH phenyl (—CH₂CH₂—)CHCONH C—CH═CH—CH═CH S I-158 COOH phenyl Et CMe Me S I-159 COOH phenyl Et CMe Me O I-160 COOH phenyl Et C—CH₂—CH₂—CH₂ S I-161 COOH phenyl Et C—CH═CH—CH═CH S I-162 COOH phenyl phenyl-CH₂CH₂S CMe Me S I-163 COOH phenyl phenyl-CH₂CH₂S CMe Me O I-164 COOH phenyl phenyl-CH₂CH₂S C—CH₂—CH₂—CH₂ S I-165 COOH phenyl phenyl-CH₂CH₂S C—CH═CH—CH═CH S I-166 COOH phenyl (4-MeS-phenyl)CH₂CH₂O CMe Me S I-167 COOH 4-Cl-phenyl (4-MeS-phenyl)CH₂CH₂O CMe Me S I-168 COOH 4-F-phenyl (4-MeS-phenyl)CH₂CH₂O CMe Me S I-169 COOH phenyl (4-MeS-phenyl)CH₂CH₂O CMe Me O I-170 COOH phenyl (4-MeS-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-171 COOH phenyl (4-MeS-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-172 CONHSO₂Me phenyl Me CMe Me S I-173 CONHSO₂Me 4-F-phenyl Me CMe Me S I-174 CONHSO₂Me 4-Cl-phenyl Me CMe Me S I-175 CONHSO₂Me phenyl Me CMe Me O I-176 CONHSO₂Me phenyl Me C—CH₂—CH₂—CH₂ S I-177 CONHSO₂Me phenyl Me C—CH═CH—CH═CH S I-178 CONHSO₂Me phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me S I-179 CONHSO₂Me 4-Cl-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me S I-180 CONHSO₂Me 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me S I-181 CONHSO₂Me phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me O I-182 CONHSO₂Me phenyl (3,4-DiMeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-183 CONHSO₂Me 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-184 CONHSO₂Me phenyl (3,4-DiMeO-phenyi)CH₂CH₂O C—CH═CH—CH═CH S I-185 COOH phenyl (4-HO-3-MeO-phenyl)CH₂CH₂O CMe Me S I-186 COOH phenyl (4-HO-3-MeO-phenyl)CH₂CH₂O CMe Me O I-187 COOH phenyl (4-HO-3-MeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-188 COOH phenyl (4-HO-3-MeO-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-189 COOH phenyl HOCH₂(HOCH)CH₂O CMe Me S I-190 COOH 4-F-phenyl HOCH₂(HOCH)CH₂O CMe Me S I-191 COOH 4-Cl-phenyl HOCH₂(HOCH)CH₂O CMe Me S I-192 COOH phenyl HOCH₂(HOCH)CH₂O CMe Me O I-193 COOH phenyl HOCH₂(HOCH)CH₂O C—CH₂—CH₂—CH₂ S I-194 COOH phenyl HOCH₂(HOCH)CH₂O C—CH═CH—CH═CH S I-195 COOH phenyl HOOCCH₂O CMe Me S I-196 COOH phenyl HOOCCH₂O CMe Me O I-197 COOH phenyl HOOCCH₂O C—CH₂—CH₂—CH₂ S I-198 COOH phenyl HOOCCH₂O C—CH═CH—CH═CH S I-199 CONHSO₂Me phenyl MeO CMe Me S I-200 CONHSO₂Me 4-F-phenyl MeO CMe Me S I-201 CONHSO₂Me 4-Cl-phenyl MeO CMe Me S I-202 CONHSO₂Me phenyl MeO CMe Me O I-203 CONHSO₂Me phenyl MeO C—CH₂—CH₂—CH₂ S I-204 CONHSO₂Me phenyl MeO C—CH═CH—CH═CH S I-205 COOH phenyl (4-EtO-3-MeO-phenyl)CH₂CH₂O CMe Me S I-206 COOH phenyl (4-EtO-3-MeO-phenyl)CH₂CH₂O CMe Me O I-207 COOH phenyl (4-EtO-3-MeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-208 COOH phenyl (4-EtO-3-MeO-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-209 COOH phenyl EtOOCCH₂O CMe Me S I-210 COOH phenyl EIOOCCH₂O CMe Me O I-211 COOH phenyl EtOOCCH₂O C—CH₂—CH₂—CH₂ S I-212 COOH phenyl EtOOCCH₂O C—CH═CH—CH═CH S I-213 COOH phenyl (3-MeO-4-EtO₂CCH₂O-phenyl)CH₂CH₂O CMe Me S I-214 COOH phenyl (3-MeO-4-EtO₂CCH₂O-phenyl)CH₂CH₂O CMe Me O I-215 COOH phenyl (3-MeO-4-EtO₂CCH₂O-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-216 COOH phenyl (3-MeO-4-EtO₂CCH₂O-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-217 COOMe phenyl MeO CMe Me S I-218 COOMe phenyl MeO CMe Me O I-219 COOMe phenyl MeO C—CH₂—CH₂—CH₂ S I-220 COOMe phenyl MeO C—CH═CH—CH═CH S I-221 COOH phenyl (4-Me-phenyl)CH₂CH₂CH₂O CMe Me S I-222 COOH phenyl (4-Me-phenyl)CH₂CH₂CH₂O CMe Me O I-223 COOH phenyl (4-Me-phenyl)CH₂CH₂CH₂O C—CH₂—CH₂—CH₂ S I-224 COOH phenyl (4-Me-phenyl)CH₂CH₂CH₂O C—CH═CH—CH═CH S I-225 COOH phenyl (4-MeO-phenyl)CH₂CH₂CH₂O CMe Me S I-226 COOH 4-Cl-phenyl (4-MeO-phenyl)CH₂CH₂CH₂O CMe Me S I-227 COOH 4-F-phenyl (4-MeO-phenyl)CH₂CH₂CH₂O CMe Me S I-228 COOH phenyl (4-MeO-phenyl)CH₂CH₂CH₂O CMe Me O I-229 COOH phenyl (4-MeO-phenyl)CH₂CH₂CH₂O C—CH₂—CH₂—CH₂ S I-230 COOH phenyl (4-MeO-phenyl)CH₂CH₂CH₂O C—CH═CH—CH═CH S I-231 COOH phenyl (4-HOOC-phenyl)CH₂CH₂CH₂O CMe Me S I-232 COOH 4-F-phenyl (4-HOOC-phenyl)CH₂CH₂CH₂O CMe Me S I-233 COOH 4-Cl-phenyl (4-HOOC-phenyl)CH₂CH₂CH₂O CMe Me S I-234 COOH phenyl (4-HOOC-phenyl)CH₂CH₂CH₂O CMe Me O I-235 COOH phenyl (4-HOOC-phenyl)CH₂CH₂CH₂O C—CH₂—CH₂—CH₂ S I-236 COOH phenyl (4-HOOC-phenyl)CH₂CH₂CH₂O C—CH═CH—CH═CH S I-237 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O CMe Me S I-238 COOH 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O CMe Me S I-239 COOH 4-Cl-phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O CMe Me S I-240 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O CMe Me O I-241 COOH 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O C—CH₂—CH₂—CH₂ S I-242 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O C—CH₂—CH₂—CH₂ S I-243 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O C—CH═CH—CH═CH S I-244 COOH phenyl (4-Cl-phenyl)CH₂CH₂CH₂O CMe Me S I-245 COOH phenyl (4-Cl-phenyl)CH₂CH₂CH₂O CMe Me O I-246 COOH phenyl (4-Cl-phenyl)CH₂CH₂CH₂O C—CH₂—CH₂—CH₂ S I-247 COOH phenyl (4-Cl-phenyl)CH₂CH₂CH₂O C—CH═CH—CH═CH S I-248 CONHSO₂phenyl phenyl MeO CMe Me S I-249 CONHSO₂phenyl 4-F-phenyl MeO CMe Me S I-250 CONHSO₂phenyl 4-Cl-phenyl MeO CMe Me S I-251 CONHSO₂phenyl phenyl MeO CMe Me O I-252 CONHSO₂phenyl 4-F-phenyl MeO C—CH₂—CH₂—CH₂ S I-253 CONHSO₂phenyl 4-Cl-phenyl MeO C—CH₂—CH₂—CH₂ S I-254 CONHSO₂phenyl phenyl MeO C—CH₂—CH₂—CH₂ S I-255 CONHSO₂phenyl phenyl MeO C—CH═CH—CH═CH S I-256 CONHSO₂phenyl phenyl Me CMe Me S I-257 CONHSO₂phenyl 4-F-phenyl Me CMe Me S I-258 CONHSO₂phenyl 4-Cl-phenyl Me CMe Me S I-259 CONHSO₂phenyl phenyl Me CMe Me O I-260 CONHSO₂phenyl phenyl Me C—CH₂—CH₂—CH₂ S I-261 CONHSO₂phenyl phenyl Me C—CH═CH—CH═CH S I-262 CONHSO₂phenyl phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me S I-263 CONHSO₂phenyl 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me S I-264 CONHSO₂phenyl 4-Cl-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me S I-265 CONHSO₂phenyl phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me O I-266 CONHSO₂phenyl phenyl (3,4-DiMeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-267 CONHSO₂phenyl phenyl (3,4-DiMeO-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-268 CONHSO₂phenyl phenyl N-Me-N-phenyl-NOCCH₂O CMe Me S I-269 CONHSO₂phenyl phenyl N-Me-N-phenyl-NOCCH₂O CMe Me O I-270 CONHSO₂phenyl phenyl N-Me-N-phenyl-NOCCH₂O C—CH₂—CH₂—CH₂ S I-271 CONHSO₂phenyl phenyl N-Me-N-phenyl-NOCCH₂O C—CH═CH—CH═CH S I-272 COOH phenyl (4-Me-phenyl)O CMe Me S I-273 COOH phenyl (4-Me-phenyl)O CMe Me O I-274 COOH phenyl (4-Me-phenyl)O C—CH₂—CH₂—CH₂ S I-275 COOH phenyl (4-Me-phenyl)O C—CH═CH—CH═CH S I-276 COOH 4-F-phenyl MeO S Me CH I-277 COOH 4-Cl-phenyl MeO S Me CH I-278 COOH phenyl MeO O Me CMe I-279 COOH phenyl MeO S Me CH I-280 COOH phenyl MeO O Me CH I-281 COOH 4-F-phenyl (4-MeO-phenyl)CH₂CH₂O S Me CH I-282 COOH 4-Cl-phenyl (4-MeO-phenyl)CH₂CH₂O O Me CMe I-283 COOH 4-Cl-phenyl (4-MeO-phenyl)CH₂CH₂O S Me CH I-284 COOH phenyl (4-MeO-phenyt)CH₂CH₂O S Me CH I-285 COOH phenyl (4-MeO-phenyl)CH₂CH₂O O Me CH I-286 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂O S Me CH I-287 COOH 4-Cl-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O S Me CH I-288 COOH 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O S Me CH I-289 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂O O Me CMe I-290 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂O O Me CH I-291 COOH phenyl (4-MeO-phenyl)CH₂O S Me CH I-292 COOH phenyl (4-MeO-phenyl)CH₂O O Me CH I-293 COOH phenyl (4-MeO-phenyl) O S Me CH I-294 COOH phenyl (4-MeO-phenyl) O O Me CH I-295 COOH phenyl (3-MeO-4-HO₂CCH₂O-phenyl)CH₂CH₂O S Me CH I-296 COOH phenyl (3-MeO-4-HO₂CCH₂O-phenyl)CH₂CH₂O O Me CMe I-297 COOH 4-F-phenyl (3-MeO-4-HO₂CCH₂O-phenyl)CH₂CH₂O S Me CH I-298 COOH 4-Cl-phenyl (3-MeO-4-HO₂CCH₂O-phenyl)CH₂CH₂O S Me CH I-299 COOH phenyl (3-MeO-4-HO₂CCH₂O-phenyl)CH₂CH₂O O Me CH I-300 COOH phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O S Me CH I-301 COOH phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O S Me CMe I-302 COOH 4-F-phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O S Me CH I-303 COOH 4-Cl-phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O S Me CH I-304 COOH phenyl (3-MeO-4-Me₂NOCCH₂O-phenyl)CH₂CH₂O O Me CH I-305 COOH phenyl (3-MeO-4-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O S Me CH I-306 COOH phenyl (4-HO₂C-phenyl)CH₂CH₂O S Me CH I-307 COOH phenyl (4-HO₂C-phenyl)CH₂CH₂O O Me CH I-308 COOH phenyl (4-HO₂C-phenyl)CH₂O S Me CH I-309 COOH phenyl (4-HO₂C-phenyl)CH₂O O Me CH I-310 COOH phenyl (4-Me-phenyl)O S Me CH I-311 COOH phenyl (4-Me-phenyl)O O Me CH I-312 COOH phenyl (4-Me-phenyl)CH₂O S Me CH I-313 COOH phenyl (4-Me-phenyl)CH₂O O Me CH I-314 COOH phenyl (4-Cl-phenyl)CH₂CH₂O S Me CH I-315 COOH phenyl (4-Cl-phenyl)CH₂CH₂O O Me CH I-316 COOH phenyl (4-Me-phenyl)CH₂CH₂O S Me CH I-317 COOH phenyl (4-Me-phenyl)CH₂CH₂O O Me CH I-318 COOH 4-F-phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O S Me CH I-319 COOH 4-Cl-phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O S Me CH I-320 COOH phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O O Me CMe I-321 COOH phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O S Me CH I-322 COOH phenyl (3-HO₂CCH₂O-phenyl)CH₂CH₂O O Me CH I-323 COOH phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O S Me CH I-324 COOH 4-F-phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O S Me CH I-325 COOH 4-Cl-phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O S Me CH I-326 COOH phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O O Me CMe I-327 COOH phenyl (3-Me₂NOCCH₂O-phenyl)CH₂CH₂O O Me CH I-328 COOH phenyl (3-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O S Me CH I-329 COOH phenyl (3-Me₂NCH₂CH₂O-phenyl)CH₂CH₂O O Me CH I-330 COOH phenyl N-Me-N-phenyl-NOCCH₂O S Me CH I-331 COOH 4-F-phenyl N-Me-N-phenyl-NOCCH₂O S Me CH I-332 COOH 4-Cl-phenyl N-Me-N-phenyl-NOCCH₂O S Me CH I-333 COOH phenyl N-Me-N-phenyl-NOCCH₂O O Me CMe I-334 COOH phenyl N-Me-N-phenyl-NOCCH₂O O Me CH I-335 COOH phenyl N-Bu-N-phenyl-NOCCH₂O S Me CH I-336 COOH phenyl N-Bu-N-phenyl-NOCCH₂O O Me CH I-337 COOH phenyl Bu₂NOCCH₂O S Me CH I-338 COOH 4-F-phenyl Bu₂NOCCH₂O S Me CH I-339 COOH 4-Cl-phenyl Bu₂NOCCH₂O S Me CH I-340 COOH phenyl Bu₂NOCCH₂O O Me CMe I-341 COOH phenyl Bu₂NOCCH₂O O Me CH I-342 COOH phenyl phenyl-HNOCCH₂O S Me CH I-343 COOH phenyl phenyl-HNOCCH₂O O Me CH I-344 COOH phenyl (2,6-diethyl-phenyl)-HNOCCH₂O S Me CH I-345 COOH 4-F-phenyl (2,6-diethyl-phenyl)-HNOCCH₂O S Me CH I-346 COOH 4-Cl-phenyl (2,6-diethyl-phenyl)-HNOCCH₂O S Me CH I-347 COOH phenyl (2,6-diethyl-phenyl)-HNOCCH₂O O Me CMe I-348 COOH phenyl (2,6-diethyl-phenyl)-HNOCCH₂O O Me CH I-349 COOH phenyl (—CH₂CH₂CH₂CH₂CH₂CH₂—)NOCCH₂O S Me CH I-350 COOH phenyl (—CH₂CH₂CH₂CH₂CH₂CH₂—)NOCCH₂O O Me CH I-351 COOH phenyl (—CH₂CH₂CH₂CH₂—)NOCCH₂O S Me CH I-352 COOH phenyl (—CH₂CH₂CH₂CH₂—)NOCCH₂O O Me CH I-353 COOH phenyl Me S Me CH I-354 COOH 4-F-phenyl Me S Me CH I-355 COOH 4-Cl-phenyl Me S Me CH I-356 COOH phenyl Me O Me CMe I-357 COOH phenyl Me O Me CH I-358 COOH phenyl MeS S Me CH I-359 COOH phenyl MeS O Me CH I-360 COOH phenyl CH₃CONH S Me CH I-361 COOH 4-F-phenyl CH₃CONH S Me CH I-362 COOH 4-Cl-phenyl CH₃CONH S Me CH I-363 COOH phenyl CH₃CONH O Me CMe I-364 COOH phenyl CH₃CONH O Me CH I-365 COOH phenyl (CH₃)₃CCONH S Me CH I-366 COOH phenyl (CH₃)₃CCONH O Me CH I-367 COOH phenyl (—CH₂CH₂—)CHCONH S Me CH I-368 COOH phenyi (—CH₂CH₂—)CHCONH O Me CH I-369 COOH phenyl Et S Me CH I-370 COOH phenyi Et O Me CH I-371 COOH phenyl phenyl-CH₂CH₂S S Me CH I-372 COOH phenyl phenyl-CH₂CH₂S O Me CH I-373 COOH phenyl (4-MeS-phenyl)CH₂CH₂O S Me CH I-374 COOH 4-F-phenyl (4-MeS-phenyl)CH₂CH₂O S Me CH I-375 COOH phenyl (4-MeS-phenyl)CH₂CH₂O O Me CMe I-376 COOH phenyl (4-MeS-phenyl)CH₂CH₂O O Me CH I-377 CONHSO₂Me phenyl Me S Me CH I-378 CONHSO₂Me 4-F-phenyl Me S Me CH I-379 CONHSO₂Me 4-Cl-phenyl Me S Me CH I-380 CONHSO₂Me phenyl Me O Me CMe I-381 CONHSO₂Me phenyl Me O Me CH I-382 CONHSO₂Me phenyl (3,4-DiMeO-phenyl)CH₂CH₂O O Me CH I-383 CONHSO₂Me 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O S Me CH I-384 CONHSO₂Me 4-Cl-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O S Me CH I-385 CONHSO₂Me phenyl (3,4-DiMeO-phenyl)CH₂CH₂O O Me CMe I-386 CONHSO₂Me phenyl (3,4-DiMeO-phenyl)CH₂CH₂O S Me CH I-387 COOH phenyl (4-HO-3-MeO-phenyl)CH₂CH₂O O Me CH I-388 COOH 4-F-phenyl (4-HO-3-MeO-phenyl)CH₂CH₂O O Me CH I-389 COOH 4-Cl-phenyl (4-HO-3-MeO-phenyl)CH₂CH₂O S Me CH I-390 COOH phenyl (4-HO-3-MeO-phenyl)CH₂CH₂O O Me CMe I-391 COOH phenyl (4-HO-3-MeO-phenyl)CH₂CH₂O S Me CH I-392 COOH phenyl HOCH₂(HOCH)CH₂O O Me CH I-393 COOH phenyl HOCH₂(HOCH)CH₂O S Me CH I-394 COOH phenyl HOOCCH₂O O Me CH I-395 COOH phenyl HOOCCH₂O S Me CH I-396 CONHSO₂Me phenyl MeO O Me CH I-397 CONHSO₂Me 4-F-phenyl MeO S Me CH I-398 CONHSO₂Me 4-Cl-phenyl MeO S Me CH I-399 CONHSO₂Me phenyl MeO O Me CMe I-400 CONHSO₂Me phenyl MeO S Me CH I-401 COOH phenyl (4-EtO-3-MeO-phenyl)CH₂CH₂O O Me CH I-402 COOH phenyl (4-EtO-3-MeO-phenyl)CH₂CH₂O S Me CH I-403 COOH phenyl EtOOCCH₂O O Me CH I-404 COOH phenyl EtOOCCH₂O S Me CH l-405 COOH phenyl (3-MeO-4-EtO₂CCH₂O-phenyl)CH₂CH₂O O Me CH I-406 COOH phenyl (3-MeO-4-EtO₂CCH₂O-phenyl)CH₂CH₂O S Me CH I-407 COOMe phenyl MeO O Me CH I-408 COOMe 4-Cl-phenyl MeO S Me CH I-409 COOMe 4-F-phenyl MeO S Me CH I-410 COOMe phenyl MeO O Me CMe I-411 COOMe phenyl MeO S Me CH I-412 COOH phenyl (4-Me-phenyl)CH₂CH₂CH₂O O Me CH I-413 COOH phenyl (4-Me-phenyl)CH₂CH₂CH₂O S Me CH I-414 COOH phenyl (4-MeO-phenyl)CH₂CH₂CH₂O O Me CH I-415 COOH phenyl (4-MeO-phenyl)CH₂CH₂CH₂O S Me CH I-416 COOH phenyl (4-HOOC-phenyl)CH₂CH₂CH₂O O Me CH I-417 COOH phenyl (4-HOOC-phenyl)CH₂CH₂CH₂O S Me CH I-418 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O O Me CH I-419 COOH 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O S Me CH I-420 COOH 4-Cl-phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O S Me CH I-421 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O O Me CMe I-422 COOH phenyl (3,4-DiMeO-phenyl)CH₂CH₂CH₂O O Me CH I-423 COOH phenyl (4-Cl-phenyl)CH₂CH₂CH₂O S Me CH I-424 COOH phenyl (4-Cl-phenyl)CH₂CH₂CH₂O O Me CH I-425 COOH phenyl (4-Me-phenyl)O S Me CH I-426 COOH phenyl (4-Me-phenyl)O O Me CH I-427 CONHSO₂phenyl phenyl MeO O Me CH I-428 CONHSO₂phenyl 4-F-phenyl MeO S Me CH I-429 CONHSO₂phenyl 4-Cl-phenyl MeO S Me CH I-430 CONHSO₂phenyl phenyl MeO O Me CMe I-431 CONHSO₂phenyl phenyl MeO S Me CH I-432 CONHSO₂phenyl phenyl Me S Me CH I-433 CONHSO₂phenyl 4-F-phenyl Me S Me CH I-434 CONHSO₂phenyl 4-Cl-phenyl Me S Me CH I-435 CONHSO₂phenyl phenyl Me O Me CMe I-436 CONHSO₂phenyl phenyl Me O Me CH I-437 CONHSO₂phenyl phenyl (3,4-DiMeO-phenyl)CH₂CH₂O O Me CH I-438 CONHSO₂phenyl 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O S Me CH I-439 CONHSO₂phenyl 4-Cl-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O S Me CH I-440 CONHSO₂phenyl phenyl (3,4-DiMeO-phenyl)CH₂CH₂O O Me CMe I-441 CONHSO₂phenyl phenyl (3,4-DiMeO-phenyl)CH₂CH₂O S Me CH I-442 COOH phenyl (2,3,4-TriMeO-phenyl)CH₂CH₂O S Me CH I-443 COOH 4-F-phenyl (2,3,4-TriMeo-phenyl)CH₂CH₂O S Me CH I-444 COOH 4-Cl-phenyl (2,3,4-TriMeO-phenyl)CH₂CH₂O S Me CH I-445 COOH phenyl (2,3,4-TriMeO-phenyl)CH₂CH₂O O Me CMe I-446 COOH phenyl (2,3,4-TriMeO-phenyl)CH₂CH₂O O Me CH I-447 COOH phenyl (iPrO-phenyl)CH₂CH₂O S Me CH I-448 COOH 4-F-phenyl (iPrO-phenyl)CH₂CH₂O S Me CH I-449 COOH 4-Cl-phenyl (IPrO-phenyl)CH₂CH₂O S Me CH I-450 COOH phenyl (iPrO-phenyl)CH₂CH₂O O Me CMe I-451 COOH phenyl (iPrO-phenyl)CH₂CH₂O O Me CH I-452 COOH phenyl nbutyl S Me CH I-453 COOH 4-F-phenyl nbutyl S Me CH I-454 COOH 4-Cl-phenyl nbutyl S Me CH I-455 COOH phenyl nbutyl O Me CMe I-456 COOH phenyl nbutyl O Me CH I-457 COOH phenyl (cyclohexyl)CH₂CH₂O S Me CH I-458 COOH 4-F-phenyl (cyclohexyl)CH₂CH₂O S Me CH I-459 COOH 4-Cl-phenyl (cyclohexyl)CH₂CH₂O S Me CH I-460 COOH phenyl (cyclohexyl)CH₂CH₂O O Me CMe I-461 COOH phenyl (cyclohexyl)CH₂CH₂O O Me CH I-462 COOH phenyl (cyclopentyl)CH₂CH₂O S Me CH I-463 COOH 4-F-phenyl (cyclopentyl)CH₂CH₂O S Me CH I-464 COOH 4-Cl-phenyl (cyclopentyl)CH₂CH₂O S Me CH I-465 COOH phenyl (cyclopentyl)CH₂CH₂O O Me CMe I-466 COOH phenyl (cyclopentyl)CH₂CH₂O O Me CH I-467 COOH phenyl CH₂CH₂-Z-CH═CHCH₂CH₂O S Me CH I-468 COOH 4-F-phenyl CH₃CH₂-Z-CH═CHCH₂CH₂O S Me CH I-469 COOH 4-Cl-phenyl CH₃CH₂-Z-CH═CHCH₂CH₂O S Me CH I-470 COOH phenyl CH₃CH₂-Z-CH═CHCH₂CH₂O O Me CMe I-471 COOH phenyl CH₃CH₂-Z-CH═CHCH₂CH₂O O Me CH I-472 COOH phenyl (3,4-dioxomethylenephenyl)CH₂CH₂O S Me CH I-473 COOH 4-F-phenyl (3,4-dioxomethylenephenyl)CH₂CH₂O S Me CH I-474 COOH 4-Cl-phenyl (3,4-dioxomethylenephenyl)CH₂CH₂O S Me CH I-475 COOH phenyl (3,4-dioxomethylenephenyl)CH₂CH₂O O Me CMe I-476 COOH phenyl (3,4-dioxomethylenephenyl)CH₂CH₂O O Me CH I-477 COOH phenyl HOCH₂CH₂ S Me CH I-478 COOH 4-F-phenyl HOCH₂CH₂ S Me CH I-479 COOH 4-Cl-phenyl HOCH₂CH₂ S Me CH I-480 COOH phenyl HOCH₂CH₂ O Me CMe I-481 COOH phenyl HOCH₂CH₂ O Me CH I-482 COOH phenyl (3,5-DiMeO-phenyl)CH₂CH₂O S Me CH I-483 COOH 4-F-phenyl (3,5-DiMeO-phenyl)CH₂CH₂O S Me CH I-484 COOH 4-Cl-phenyl (3,5-DiMeO-phenyl)CH₂CH₂O S Me CH I-485 COOH phenyl (3,5-DiMeO-phenyl)CH₂CH₂O O Me CMe I-486 COOH phenyl (3,5-DiMeO-phenyl)CH₂CH₂O O Me CH I-487 COOH phenyl (3,5-DiMeO-phenyl)CH₂CH₂O CMe Me S I-488 COOH 4-Cl-phenyl (3,5-DiMeO-phenyl)CH₂CH₂O CMe Me S I-489 COOH 4-F-phenyl (3,5-DiMeO-phenyl)CH₂CH₂O CMe Me S I-490 COOH phenyl (3,5-DiMeO-phenyl)CH₂CH₂O CMe Me O I-491 COOH phenyl (3,5-DiMeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-492 COOH phenyl HOCH₂CH₂ CMe Me S I-493 COOH phenyl HOCH₂CH₂ CMe Me O I-494 COOH 4-F-phenyl HOCH₂CH₂ CMe Me S I-495 COOH 4-Cl-phenyl HOCH₂CH₂ CMe Me O I-496 COOH phenyl HOCH₂CH₂ C—CH₂—CH₂—CH₂ S I-497 COOH phenyl (3,4-dioxomethylenephenyl)CH₂CH₂O CMe Me S I-498 COOH 4-F-phenyl (3,4-dioxomethylenephenyl)CH₂CH₂O CMe Me S I-499 COOH phenyl (3,4-dioxomethylenephenyl)CH₂CH₂O CMe Me O I-500 COOH 4-F-phenyl (3,4-dioxomethylenephenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-501 COOH phenyl (3,4-dioxomethylenephenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-502 COOH phenyl CH₃CH₂-Z-CH═CHCH₂CH₂O CMe Me S I-503 COOH 4-F-phenyl CH₃CH₂-Z-CH═CHCH₂CH₂O CMe Me S I-504 COOH 4-Cl-phenyl CH₃CH₂-Z-CH═CHCH₂CH₂O CMe Me S I-505 COOH phenyl CH₃CH₂-Z-CH═CHCH₂CH₂O CMe Me O I-506 COOH phenyl CH₃CH₂-Z-CH═CHCH₂CH₂O C—CH₂—CH₂—CH₂ S I-507 COOH phenyl (cyclopentyl)CH₂CH₂O CMe Me S I-508 COOH phenyl (cyclopentyl)CH₂CH₂O CMe Me O I-509 COOH phenyl (cyclopentyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-510 COOH phenyl (cyclopentyl)CH₂CH₂O C—CH═CH—CH═CH S I-511 COOH phenyl (cyclohexyl)CH₂CH₂O CMe Me S I-512 COOH 4-Cl-phenyl (cyclohexyl)CH₂CH₂O CMe Me S I-513 COOH phenyl (cyclohexyl)CH₂CH₂O CMe Me O I-514 COOH 4-F-phenyl (cyclohexyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-515 COOH phenyl (cyclohexyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-516 COOH 4-F-phenyl n-butyl CMe Me S I-517 COOH phenyl n-butyl CMe Me S I-518 COOH phenyl n-butyl CMe Me O I-519 COOH 4-Cl-phenyl n-butyl C—CH₂—CH₂—CH₂ S I-520 COOH phenyl n-butyl C—CH₂—CH₂—CH₂ S I-521 COOH phenyl (2,3,4-TriMeO-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-522 COOH phenyl (2,3,4-TriMeO-phenyl)CH₂CH₂O CMe Me S I-523 COOH 4-F-phenyl (2,3,4-TriMeO-phenyl)CH₂CH₂O CMe Me S I-524 COOH 4-Cl-phenyl (2,3,4-TriMeO-phenyl)CH₂CH₂O CMe Me S I-525 COOH phenyl (2,3,4-TriMeO-phenyl)CH₂CH₂O CMe Me O I-526 COOH phenyl (iPrO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-527 COOH phenyl (iPrO-phenyl)CH₂CH₂O CMe Me S I-528 COOH phenyl (iPrO-phenyl)CH₂CH₂O CMe Me O I-529 COOH phenyl (iPrO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-530 COOH phenyl (iPrO-phenyl)CH₂CH₂O C—CH═CH—CH═CH S I-531 CONHSO₂phenyl phenyl MeO CMe Me S I-532 CONHSO₂phenyl 4-Cl -phenyl MeO CMe Me S I-533 CONHSO₂phenyl 4-F-phenyl MeO CMe Me S I-534 CONHSO₂phenyl phenyl MeO CMe Me O I-535 CONHSO₂phenyl phenyl MeO C—CH₂—CH₂—CH₂ S I-536 CONHSO₂phenyl phenyl Me CMe Me S I-537 CONHSO₂phenyl phenyl Me CMe Me O I-538 CONHSO₂phenyl 4-F-phenyl Me CMe Me S I-539 CONHSO₂phenyl 4-Cl-phenyl Me CMe Me O I-540 CONHSO₂phenyl phenyl Me C—CH₂—CH₂—CH₂ S I-541 CONHSO₂phenyl phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me S I-542 CONHSO₂phenyl 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me S I-543 CONHSO₂phenyl phenyl (3,4-DiMeO-phenyl)CH₂CH₂O CMe Me O I-544 CONHSO₂phenyl 4-F-phenyl (3,4-DiMeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-545 CONHSO₂phenyl phenyl (3,4-DiMeO-phenyl)CH₂CH₂O C—CH₂—CH₂—CH₂ S I-546 COOH phenyl, 4-Cl-phenyl MeO CMe Me S I-547 COOH 4-Cl-phenyl, 4-F-phenyl MeO CMe Me S I-548 COOH 4-F-phenyl, phenyl MeO CMe Me S I-549 COOH 4-Me-phenyl, naphthyl MeO CMe Me O I-550 COOH 2-F-phenyl, phenyl MeO C—CH₂—CH₂—CH₂ S I-551 COOH 2-F-phenyl, 4-Me-phenyl MeO C—CH═CH—CH═CH S I-552 COOH naphthyl, phenyl (4-MeO-phenyl)CH₂CH₂O CMe Me S I-553 COOH phenyl, 4-Cl-phenyl CH₃CH₂O CMe Me S I-554 COOH 4-Cl-phenyl, 4-F-phenyl CH₃CH₂O CMe Me S I-555 COOH 4-F-phenyl, phenyl ipropylO CMe Me S I-556 COOH naphthyl, naphthyl MeO CMe Me S I-557 COOH naphthyl, naphthyl MeO C—CH₂—CH₂—CH₂ S I-558 COOH 4-F-phenyl, 4-Cl-phenyl (4-MeO-phenyl)CH₂CH₂O CMe Me O

Example 7

According to the binding test described above, receptor binding data were measured for the compounds shown below.

The results are shown in Table 2.

Table 2

Receptor binding data (K_(i) values)

Compound ET_(A) [nM/1] ET_(B) [nM/1] I-1 13 650  I-15 215 485 I-6 900 >7100 I-5 50 >700 I-4 29 3100  I-13 145 210 

We claim:
 1. A heterocyclically substituted α-hydroxycarboxylic acid derivative

where R¹ is tetrazole or a group

where R has the following meanings: a) a radical OR⁵, where R⁵ is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerable organic ammonium ion; C₃-C₈-cycloalkyl, C₁-C₈-alkyl, CH₂-phenyl, C₃-C₈-alkenyl, C₃-C₈-alkynyl or phenyl, in each case unsubstituted or substituted; b) a five-membered heteroaromatic linked via a nitrogen atom; c) a group

 in which k can assume the values 0, 1 or 2, p can assume the values 1, 2, 3 or 4 and R⁶ is C₁-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-alkenyl, C₃-C₈-alkynyl or unsubstituted or substituted phenyl; d) a radical

 where R⁷ is: C₁-C₄-alkyl, C₃-C₈-alkenyl, C₃-C₈-alkynyl, C₃-C₈-cycloalkyl, it being possible for these radicals to carry a C₂-C₄-alkoxy, C₁-C₄-alkylthio and/or a phenyl radical; C₁-C₄-haloalkyl or phenyl, which is unsubstituted or substituted; A is NR⁸R⁹, azido, OR¹⁰, SR¹⁰ or C₁-C₄-alkyl X is oxygen, sulfur, CR¹¹ or NR¹²; with the proviso that if X=CR¹¹, then Y=oxygen or sulfur or NR¹⁴; Y is oxygen, sulfur, CR¹³ or NR¹⁴; with the proviso that if Y=oxygen or sulfur or NR¹⁴, then X=CR¹¹; R² and R³ (which can be identical or different): are phenyl or naphthyl, which is unsubstituted or substituted, or phenyl or naphthyl, which are connected to one another in the ortho-position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂, NH or N(C₁-C₄-alkyl) group C₅-C₆-cycloalkyl, which is unsubstituted or substituted; R⁴ and R¹¹ (which can be identical or different): are hydrogen, halogen, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, hydroxyl, NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂ C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, it being possible for these radicals to be unsubstituted or substituted; or CR⁴, together with CR¹¹, forms a 5- or 6-membered alkylene or alkenylene ring, which can be unsubstituted or substituted, and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, —NH or —N(C₁-C₄-alkyl); R⁸ is hydrogen, C₁-C₈-alkyl, C₃-C₈-alkenyl, C₃-C₈-alkynyl, C₁-C₅-alkylcarbonyl, it being possible for these radicals to be unsubstituted or substituted; phenyl or naphthyl, which is unsubstituted or substituted; unsubstituted or substituted C₃-C₈-cycloalkyl; or R⁸, together with R⁹, forms a C₃-C₇-alkylene chain, which can be unsubstituted or substituted and is closed to give a ring, and in which an alkylene group can be replaced by oxygen or sulfur; R⁹ is hydrogen, C₁-C₄-alkyl; or R⁹ is linked with R⁸ as indicated under R⁸ to give a ring; R¹⁰ is hydrogen, C₁-C₈-alkyl, C₃-C₈-alkenyl, C₃-C₈-alkynyl, it being possible for these radicals to be unsubstituted or substituted; phenyl or naphthyl, which is unsubstituted or substituted; unsubstituted or substituted C₃-C₈-cycloalkyl; R¹² is hydrogen, C₁-C₄-alkyl; or NR¹², together with CR⁴, forms a 5- or 6-membered alkylene or alkenylene ring, which can be unsubstituted or substituted, and in which in each case one or more methylene groups can be replaced by oxygen or sulfur; R¹³ is hydrogen, halogen, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, it being possible for these radicals to be unsubstituted or substituted; R¹⁴ is hydrogen, C₁-C₄-alkyl; and the physiologically tolerable salts, and the possible enantiomerically pure and diastereoisomerically pure forms.
 2. The method of claim 1, which is a method for treating chronic cardiac insufficiency, restenosis, high blood pressure, high pulmonary pressure, acute/chronic kidney failure, cerebral ischemia, asthma, benign prostate hyperplasia or prostate cancer.
 3. A combination of heterocyclically substituted α-hydroxycarboxylic acid derivatives I as claimed in claim 1 and one or more active compounds selected from inhibitors of the renin-angiotensin system such as renin inhibitors, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, mixed ACE/neutral endopeptidase (NEP) inhibitors, β-blockers, diuretics, calcium antagonists and VEGF-blocking substances.
 4. A pharmaceutical preparation for oral and parenteral use, comprising per individual dose, in addition to the customary drug auxiliaries, at least one carboxylic acid derivative I as claimed in claim
 1. 5. A method of inhibiting the binding of endothelin to endothelin receptors in a subject in need of such inhibition, which comprises administering to said subject an effective amount of at least one of the heterocyclically substituted α-hydroxycarboxylic acid derivatives of claim
 1. 